Abstract
Plasmodium vivax is a major cause of febrile illness in endemic areas of Asia, Central and South America, and the horn of Africa. Plasmodium vivax infections are characterized by relapses of malaria arising from persistent liver stages of the parasite (hypnozoites) which can be prevented only by 8-aminoquinoline anti-malarials. Tropical P. vivax relapses at three week intervals if rapidly eliminated anti-malarials are given for treatment, whereas in temperate regions and parts of the sub-tropics P. vivax infections are characterized either by a long incubation or a long-latency period between illness and relapse - in both cases approximating 8-10 months. The epidemiology of the different relapse phenotypes has not been defined adequately despite obvious relevance to malaria control and elimination. The number of sporozoites inoculated by the anopheline mosquito is an important determinant of both the timing and the number of relapses. The intervals between relapses display a remarkable periodicity which has not been explained. Evidence is presented that the proportion of patients who have successive relapses is relatively constant and that the factor which activates hypnozoites and leads to regular interval relapse in vivax malaria is the systemic febrile illness itself. It is proposed that in endemic areas a large proportion of the population harbours latent hypnozoites which can be activated by a systemic illness such as vivax or falciparum malaria. This explains the high rates of vivax following falciparum malaria, the high proportion of heterologous genotypes in relapses, the higher rates of relapse in people living in endemic areas compared with artificial infection studies, and, by facilitating recombination between different genotypes, contributes to P. vivax genetic diversity particularly in low transmission settings. Long-latency P. vivax phenotypes may be more widespread and more prevalent than currently thought. These observations have important implications for the assessment of radical treatment efficacy and for malaria control and elimination.
Highlights
In endemic areas of Asia, Oceania, Central and South America, and in the horn of Africa Plasmodium vivax malaria is a major cause of morbidity
Relapses of vivax malaria arise from activation of latent hypnozoites (ALH) Swellengrebel and de Buck [17] noted that relapse rates were higher in naturally acquired P. vivax infections than in mosquito-borne infections with the local strains in neurosyphilis patients
Space-time clustering of infections may occur in low transmission areas it is implausible that over 20% of P. falciparum inoculations would be associated with a separate P. vivax inoculation within one or two days, when individuals receive on average less than one infectious bite per year
Summary
In endemic areas of Asia, Oceania, Central and South America, and in the horn of Africa Plasmodium vivax malaria is a major cause of morbidity. In the more prevalent tropical strains of P. vivax treated in soldiers fighting in the Indo-Burmese and South-West Pacific campaigns in the Second World War, the relapses were documented to occur at intervals of 3 to 4 weeks (as in the Chesson strain) [42,43,44,45,46,47,48,49,50,51,52,76] These observations were similar to those in the seminal chemotherapy studies of Sinton and Figure 7 Schematic diagram by Hankey et al [79]of relapse patterns following Korean vivax malaria (upper panel) and tropical frequent relapse P. vivax (lower panel).
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